今日の臨床サポート

抗精神病薬の副作用のマネジメント

著者: 竹内啓善 慶應義塾大学医学部 精神・神経科学教室

監修: 上島国利 昭和大学

著者校正済:2022/11/09
現在監修レビュー中
参考ガイドライン:
  1. David M.Taylor et al編, 内田裕之ほか訳:モーズレイ処方ガイドライン 第14版, 2022
患者向け説明資料

概要・推奨   

  1. 抗精神病薬の主要な副作用のうち、錐体外路症状(パーキンソン症候群、急性ジストニア、アカシジア、遅発性ジスキネジア)はどの抗精神病薬でも出現し得るが、第1世代抗精神病薬(first-generation antipsychotics:FGA)(特に高力価)で多くみられる。
  1. 第2世代抗精神病薬(second-generation antipsychotics:SGA)は、遅発性ジスキネジアを含め、錐体外路症状のリスクがFGAよりも低いため、統合失調症治療の第1選択薬として推奨される(推奨度2)
  1. 代表的なSGAのうち、錐体外路症状のリスクが最も高いのはリスペリドン/パリペリドン、次いでアリピプラゾール、クエチアピン、オランザピン、最も低いのはクロザピンである。このため、錐体外路症状に対応が必要な場合、相対的リスクが低いSGAへの変更が考慮される(推奨度2)
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
竹内啓善 : 講演料(大塚製薬,大日本住友製薬,ヤンセンファーマ)[2022年]
監修:上島国利 : 原稿料(大日本住友製薬)[2022年]

改訂のポイント:
  1. モーズレイ処方ガイドライン 第14版に基づき、図表を更新した。
  1. 概要・推奨欄にクロザピンの副作用について加筆した。

まとめ

副作用のまとめ  
  1. 抗精神病薬の主要な副作用のうち、錐体外路症状(パーキンソン症候群、急性ジストニア、アカシジア、遅発性ジスキネジア)はどの抗精神病薬でも出現し得るが、第1世代抗精神病薬(first-generation antipsychotics:FGA)(特に高力価)で多くみられる。
  1. 高プロラクチン血症はどの抗精神病薬でも出現し得るが、FGA、リスペリドン/パリペリドンで多くみられる。
  1. 代謝系副作用(体重増加、糖代謝異常・糖尿病、脂質代謝異常・高脂血症)はどの抗精神病薬でも出現し得るが、アリピプラゾール以外の第2世代抗精神病薬(second-generation antipsychotics:SGA)、低力価のFGAで多くみられる。
  1. このほか、QT延長、悪性症候群、多飲症、性機能障害、抗コリン症状(口渇、便秘、霧視など)、眠気などさまざまな副作用がある。
 
各抗精神病薬の副作用プロフィール

モーズレイ処方ガイドラインの各抗精神病薬の副作用プロフィール一覧を示す。

問診・診察のポイント  
  1. 錐体外路症状は、特に視診が重要になる。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

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文献 

Stefan Leucht, Caroline Corves, Dieter Arbter, Rolf R Engel, Chunbo Li, John M Davis
Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis.
Lancet. 2009 Jan 3;373(9657):31-41. doi: 10.1016/S0140-6736(08)61764-X. Epub 2008 Dec 6.
Abstract/Text BACKGROUND: Because of the debate about whether second-generation antipsychotic drugs are better than first-generation antipsychotic drugs, we did a meta-analysis of randomised controlled trials to compare the effects of these two types of drugs in patients with schizophrenia.
METHODS: We compared nine second-generation antipsychotic drugs with first-generation drugs for overall efficacy (main outcome), positive, negative and depressive symptoms, relapse, quality of life, extrapyramidal side-effects, weight gain, and sedation.
FINDINGS: We included 150 double-blind, mostly short-term, studies, with 21 533 participants. We excluded open studies because they systematically favoured second-generation drugs. Four of these drugs were better than first-generation antipsychotic drugs for overall efficacy, with small to medium effect sizes (amisulpride -0.31 [95% CI -0.44 to -0.19, p<0.0001], clozapine -0.52 [-0.75 to -0.29, p<0.0001], olanzapine -0.28 [-0.38 to -0.18, p<0.0001], and risperidone -0.13 [-0.22 to -0.05, p=0.002]). The other second-generation drugs were not more efficacious than the first-generation drugs, even for negative symptoms. Therefore efficacy on negative symptoms cannot be a core component of atypicality. Second-generation antipsychotic drugs induced fewer extrapyramidal side-effects than did haloperidol (even at low doses). Only a few have been shown to induce fewer extrapyramidal side-effects than low-potency first-generation antipsychotic drugs. With the exception of aripiprazole and ziprasidone, second-generation antipsychotic drugs induced more weight gain, in various degrees, than did haloperidol but not than low-potency first-generation drugs. The second-generation drugs also differed in their sedating properties. We did not note any consistent effects of moderator variables, such as industry sponsorship, comparator dose, or prophylactic antiparkinsonian medication.
INTERPRETATION: Second-generation antipsychotic drugs differ in many properties and are not a homogeneous class. This meta-analysis provides data for individualised treatment based on efficacy, side-effects, and cost.

PMID 19058842
Maren Carbon, John M Kane, Stefan Leucht, Christoph U Correll
Tardive dyskinesia risk with first- and second-generation antipsychotics in comparative randomized controlled trials: a meta-analysis.
World Psychiatry. 2018 Oct;17(3):330-340. doi: 10.1002/wps.20579.
Abstract/Text Tardive dyskinesia (TD) risk with D2/serotonin receptor antagonists or D2 receptor partial agonists (second-generation antipsychotics, SGAs) is considered significantly lower than with D2 antagonists (first-generation antipsychotics, FGAs). As some reports questioned this notion, we meta-analyzed randomized controlled studies (RCTs) to estimate the risk ratio (RR) and annualized rate ratio (RaR) of TD comparing SGAs vs. FGAs and SGAs vs. SGAs. Additionally, we calculated raw and annualized pooled TD rates for each antipsychotic. Data from 57 head-to-head RCTs, including 32 FGA and 86 SGA arms, were meta-analyzed, yielding 32 FGA-SGA pairs and 35 SGA-SGA pairs. The annualized TD incidence across FGA arms was 6.5% (95% CI: 5.3-7.8%) vs. 2.6% (95% CI: 2.0-3.1%) across SGA arms. TD risk and annualized rates were lower with SGAs vs. FGAs (RR=0.47, 95% CI: 0.39-0.57, p<0.0001, k=28; RaR=0.35, 95% CI: 0.28-0.45, p<0.0001, number-needed-to-treat, NNT=20). Meta-regression showed no FGA dose effect on FGA-SGA comparisons (Z=-1.03, p=0.30). FGA-SGA TD RaRs differed by SGA comparator (Q=21.8, df=7, p=0.003), with a significant advantage of olanzapine and aripiprazole over other non-clozapine SGAs in exploratory pairwise comparisons. SGA-SGA comparisons confirmed the olanzapine advantage vs. non-clozapine SGAs (RaR=0.66, 95% CI: 0.49-0.88, p=0.006, k=17, NNT=100). This meta-analysis confirms a clinically meaningfully lower TD risk with SGAs vs. FGAs, which is not driven by high dose FGA comparators, and documents significant differences with respect to this risk between individual SGAs.

© 2018 World Psychiatric Association.
PMID 30192088
Maximilian Huhn, Adriani Nikolakopoulou, Johannes Schneider-Thoma, Marc Krause, Myrto Samara, Natalie Peter, Thomas Arndt, Lio Bäckers, Philipp Rothe, Andrea Cipriani, John Davis, Georgia Salanti, Stefan Leucht
Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis.
Lancet. 2019 Sep 14;394(10202):939-951. doi: 10.1016/S0140-6736(19)31135-3. Epub 2019 Jul 11.
Abstract/Text BACKGROUND: Schizophrenia is one of the most common, burdensome, and costly psychiatric disorders in adults worldwide. Antipsychotic drugs are its treatment of choice, but there is controversy about which agent should be used. We aimed to compare and rank antipsychotics by quantifying information from randomised controlled trials.
METHODS: We did a network meta-analysis of placebo-controlled and head-to-head randomised controlled trials and compared 32 antipsychotics. We searched Embase, MEDLINE, PsycINFO, PubMed, BIOSIS, Cochrane Central Register of Controlled Trials (CENTRAL), WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov from database inception to Jan 8, 2019. Two authors independently selected studies and extracted data. We included randomised controlled trials in adults with acute symptoms of schizophrenia or related disorders. We excluded studies in patients with treatment resistance, first episode, predominant negative or depressive symptoms, concomitant medical illnesses, and relapse-prevention studies. Our primary outcome was change in overall symptoms measured with standardised rating scales. We also extracted data for eight efficacy and eight safety outcomes. Differences in the findings of the studies were explored in metaregressions and sensitivity analyses. Effect size measures were standardised mean differences, mean differences, or risk ratios with 95% credible intervals (CrIs). Confidence in the evidence was assessed using CINeMA (Confidence in Network Meta-Analysis). The study protocol is registered with PROSPERO, number CRD42014014919.
FINDINGS: We identified 54 417 citations and included 402 studies with data for 53 463 participants. Effect size estimates suggested all antipsychotics reduced overall symptoms more than placebo (although not statistically significant for six drugs), with standardised mean differences ranging from -0·89 (95% CrI -1·08 to -0·71) for clozapine to -0·03 (-0·59 to 0·52) for levomepromazine (40 815 participants). Standardised mean differences compared with placebo for reduction of positive symptoms (31 179 participants) varied from -0·69 (95% CrI -0·86 to -0·52) for amisulpride to -0·17 (-0·31 to -0·04) for brexpiprazole, for negative symptoms (32 015 participants) from -0·62 (-0·84 to -0·39; clozapine) to -0·10 (-0·45 to 0·25; flupentixol), for depressive symptoms (19 683 participants) from -0·90 (-1·36 to -0·44; sulpiride) to 0·04 (-0·39 to 0·47; flupentixol). Risk ratios compared with placebo for all-cause discontinuation (42 672 participants) ranged from 0·52 (0·12 to 0·95; clopenthixol) to 1·15 (0·36 to 1·47; pimozide), for sedation (30 770 participants) from 0·92 (0·17 to 2·03; pimozide) to 10·20 (4·72 to 29·41; zuclopenthixol), for use of antiparkinson medication (24 911 participants) from 0·46 (0·19 to 0·88; clozapine) to 6·14 (4·81 to 6·55; pimozide). Mean differences compared to placebo for weight gain (28 317 participants) ranged from -0·16 kg (-0·73 to 0·40; ziprasidone) to 3·21 kg (2·10 to 4·31; zotepine), for prolactin elevation (21 569 participants) from -77·05 ng/mL (-120·23 to -33·54; clozapine) to 48·51 ng/mL (43·52 to 53·51; paliperidone) and for QTc prolongation (15 467 participants) from -2·21 ms (-4·54 to 0·15; lurasidone) to 23·90 ms (20·56 to 27·33; sertindole). Conclusions for the primary outcome did not substantially change after adjusting for possible effect moderators or in sensitivity analyses (eg, when excluding placebo-controlled studies). The confidence in evidence was often low or very low.
INTERPRETATION: There are some efficacy differences between antipsychotics, but most of them are gradual rather than discrete. Differences in side-effects are more marked. These findings will aid clinicians in balancing risks versus benefits of those drugs available in their countries. They should consider the importance of each outcome, the patients' medical problems, and preferences.
FUNDING: German Ministry of Education and Research and National Institute for Health Research.

Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
PMID 31303314
J Rathbone, K Soares-Weiser
Anticholinergics for neuroleptic-induced acute akathisia.
Cochrane Database Syst Rev. 2006 Oct 18;(4):CD003727. doi: 10.1002/14651858.CD003727.pub3. Epub 2006 Oct 18.
Abstract/Text BACKGROUND: Neuroleptic-induced akathisia is one of the most common and distressing early-onset adverse effects of first generation 'typical' antipsychotic drugs. It is associated with poor compliance with treatment, and thus, ultimately, with an increased risk of relapse. We assessed the role of anticholinergic drugs as an adjunct therapy to standard antipsychotic medication in the pharmacological treatment of this adverse effect.
OBJECTIVES: To review anticholinergic drugs for neuroleptic-induced acute akathisia.
SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group's Register (October 1999), Biological Abstracts (1982-1999), CINAHL (1982-1999), Cochrane Library (Issue 4 1999), EMBASE (1980-1999), LILACS (1982-1999), MEDLINE (1966-1999) and PsycLIT (1974-1999). References of all identified studies were inspected for more trials and we contacted first authors. Each included study was sought as a citation on the Science Citation Index database. For this 2005-6 update, we searched the Cochrane Schizophrenia Group's Register (July 2005).
SELECTION CRITERIA: We included all randomised clinical trials of adjunctive anticholinergic drugs in addition to antipsychotic medication compared with placebo, for people with neuroleptic-induced acute akathisia.
DATA COLLECTION AND ANALYSIS: We quality assessed and extracted data independently. We calculated the fixed effects relative risk (RR), the 95% confidence intervals (CI) and, where appropriate, the number needed to treat (NNT) for homogeneous dichotomous data on an intention-to-treat basis. For continuous data, we calculated weighted mean differences (WMD).
MAIN RESULTS: We identified no relevant randomised controlled trials.
AUTHORS' CONCLUSIONS: At present, there is no reliable evidence to support or refute the use of anticholinergics for people suffering from neuroleptic-induced acute akathisia. Akathisia is a distressing movement disorder that remains highly prevalent in people with schizophrenia, both in the developed and developing world. This review highlights the need for well designed, conducted and reported clinical trials to address the claims of open studies as regards the effects of the anticholinergic group of drugs for akathisia.

PMID 17054182
Bora Baskak, E Cem Atbasoglu, Halise Devrimci Ozguven, Meram Can Saka, Ali Kemal Gogus
The effectiveness of intramuscular biperiden in acute akathisia: a double-blind, randomized, placebo-controlled study.
J Clin Psychopharmacol. 2007 Jun;27(3):289-94. doi: 10.1097/jcp.0b013e3180582439.
Abstract/Text Neuroleptic-induced acute akathisia (NIA) is a distressing condition and an important clinical problem because it is associated with treatment noncompliance and suicidal or impulsive behavior. Anticholinergics are among the treatment options; however, a review of the literature fails to identify a double-blind, randomized, placebo-controlled study of these medications in NIA. In a randomized, double-blind, placebo-controlled design, we studied the effectiveness of intramuscular biperiden (n = 15) or isotonic saline (n = 15) in the treatment of NIA diagnosed with the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria. Injections were repeated up to 3 times unless akathisia was completely treated (scored 0 for global akathisia with the Barnes Akathisia Rating Scale). Patients were assessed for akathisia, other movement disorders, and psychiatric symptoms at baseline and 3 times after the first injection at 2-hour intervals. Response was defined as at least a 2-point decline in the global akathisia score. The numbers of responders in the 2 groups were not significantly different (7 and 5 in the biperiden and placebo groups, respectively). The courses of individual items on the Barnes Akathisia Rating Scale were also similar. Our results suggest that intramuscular biperiden should not be considered as a first-line treatment of NIA.

PMID 17502777
A R Lima, J Bacalcthuk, T R E Barnes, K Soares-Weiser
Central action beta-blockers versus placebo for neuroleptic-induced acute akathisia.
Cochrane Database Syst Rev. 2004 Oct 18;(4):CD001946. doi: 10.1002/14651858.CD001946.pub2. Epub 2004 Oct 18.
Abstract/Text BACKGROUND: Neuroleptic-induced akathisia is a common, distressing early-onset adverse effect of neuroleptic drugs. It has been associated with poor treatment compliance and an increased risk of relapse.
OBJECTIVES: To determine the effects of central action beta-blockers compared with placebo for people with neuroleptic-induced acute akathisia.
SEARCH STRATEGY: We updated previous searches of the Cochrane Schizophrenia Group Register (May 1999), Biological Abstracts (January 1982-March 1999), The Cochrane Library (issue 3 1999), EMBASE (January 1980-March 1999), LILACS (January 1982-March 1999), MEDLINE (January 1964-March 1999), PsycLIT (January 1974-March 1999), and SCISEARCH by searching the Cochrane Schizophrenia Group Register (November 2003). We sought further references from published trials and their authors.
SELECTION CRITERIA: We included all randomised controlled clinical trials of central action beta-blockers versus placebo for people with neuroleptic-induced acute akathisia.
DATA COLLECTION AND ANALYSIS: Working independently, we selected and critically appraised studies, extracted data and analysed on an intention-to-treat basis. Where possible and appropriate we calculated risk ratios (RR) and their 95% confidence intervals (CI) with the number needed to treat (NNT). For continuous data we calculated Weighted Mean Differences (WMD).
MAIN RESULTS: We identified three randomised controlled trials (total n=51, maximum duration 72 hours). We were not able to draw any firm conclusions from such a small data set. In the two 48 hour studies no-one experienced full remission of akathisia, and only one person in each group experienced a 50% remission (n=11, 1 RCT, RR 1.04 CI 0.59 -1.83). One trial stated that no adverse effects occurred in the two groups (n=20, 1 RCT, RR not estimable). The 72 hour study did not show any statistical difference between the central acting beta-blocker (ICI 118,551) and placebo for the outcome 'no change/worse' (n=10, RR 0.22 CI 0.0 to 1.5).
REVIEWERS' CONCLUSIONS: There are insufficient data to recommend beta-blocking drugs for akathisia. These drugs are experimental for this problem, and this review highlights the need for more evaluative studies.

PMID 15495022
A R Lima, K Soares-Weiser, J Bacaltchuk, T R Barnes
Benzodiazepines for neuroleptic-induced acute akathisia.
Cochrane Database Syst Rev. 2002;(1):CD001950. doi: 10.1002/14651858.CD001950.
Abstract/Text BACKGROUND: Neuroleptic-induced akathisia is one of the most common and distressing early-onset adverse effects of antipsychotic drugs, being associated with poor compliance with treatment, and thus, ultimately, to an increase risk of relapse. This review assesses the role of benzodiazepines in the pharmacological treatment of this problem.
OBJECTIVES: To determine the effects of benzodiazepines versus placebo for people with neuroleptic-induced acute akathisia.
SEARCH STRATEGY: Biological Abstracts (January 1982-March 1999), The Cochrane Library (Issue 3 1999), The Cochrane Schizophrenia Group's Register (May 2001), EMBASE (January 1980-March 1999), LILACS (January 1982-March 1999), MEDLINE (January 1964-March 1999), PsycLIT (January 1974-March 1999), and SCISEARCH were searched. Further references were sought from published trials and their authors.
SELECTION CRITERIA: All randomised clinical trials comparing benzodiazepines with placebo for people with antipsychotic-induced acute akathisia.
DATA COLLECTION AND ANALYSIS: Two reviewers, working independently, selected, quality assessed and extracted data. These data were then analysed on an intention-to-treat basis. For homogeneous dichotomous data the fixed effects relative risk (RR), the 95% confidence intervals (CI) and, where appropriate, the number needed to treat (NNT) were calculated on an intention-to-treat basis. For continuous data, reviewers calculated weighted mean differences.
MAIN RESULTS: Two small (total N=27) randomised controlled trials were included. By seven to 14 days, there was a reduction in symptoms for those patients receiving clonazepam compared with placebo (2 RCTs, N=26, RR 0.09 CI 0.01 to 0.6, NNT 1.2 CI 0.9 to 1.5). No significant difference was found for adverse events (2 RCTs, N=26, RR 3.00 CI 0.2 to 62) or the need for anticholinergic medication (2 RCTs, N=26, RR 1.56 CI 0.9 to 2.7). No one left the two studies early. Data on mental, social and family outcomes could not be pooled and there was little or no data on user satisfaction, deaths, violence, criminal behaviour and costs.
REVIEWER'S CONCLUSIONS: Over a short follow-up period, the use of benzodiazepines may reduce the symptoms of antipsychotic-induced acute akathisia. This review highlights the need for well designed, conducted and reported clinical trials to address the claims of open studies.

PMID 11869614
Hiroyoshi Takeuchi, Yasuhiro Mori, Yuichiro Tsutsumi
Pathophysiology, prognosis and treatment of tardive dyskinesia.
Ther Adv Psychopharmacol. 2022;12:20451253221117313. doi: 10.1177/20451253221117313. Epub 2022 Oct 21.
Abstract/Text Tardive dyskinesia (TD), a movement disorder associated with antipsychotics, most frequently affects the lower face and jaw muscles, but can also affect walking, breathing and use of the hands and limbs. Knowledge of TD among physicians may be limited, and the pathophysiology of TD is poorly understood. We conducted this review to summarise the current knowledge surrounding the pathophysiology of TD and present recommendations for prevention and treatment based on a literature search and roundtable discussion attended by psychiatrists in Japan. It has been suggested that dopamine hypersensitivity, damaged gamma-aminobutyric acidergic neurons and/or increased production of reactive oxygen species may contribute to development of TD. Symptoms can profoundly affect everyday life; patients who develop TD have poorer prognoses, worse health-related quality of life, greater social withdrawal and higher mortality than patients without TD. Traditional treatment options include dietary supplements, although evidence for their effectiveness is low. Among pharmaceutical interventions, there is moderate evidence that switching to the second-generation antipsychotic clozapine, which has a lower affinity for dopamine D2 receptors than other antipsychotics, may improve symptoms. Vesicular monoamine transporter 2 (VMAT-2) inhibitors, which oppose the increased dopaminergic activity associated with prolonged antipsychotic use by interfering with dopamine uptake and storage, have the strongest evidence for efficacy. VMAT-2 inhibitors are approved in the United States for the treatment of TD, and the first VMAT-2 inhibitor was approved in Japan for this indication in March 2022. Most guidelines recommend treating TD by first reducing the dose of antipsychotics or switching to clozapine or other second-generation antipsychotics, which have a lower association with TD than first-generation antipsychotics. We recommend focusing on prevention and monitoring for TD when prescribing antipsychotics, given that TD is often irreversible. Physicians should treat with antipsychotics only when necessary and at the lowest effective dose, and frequently monitor for TD symptoms.
Plain Language Summary: Plain Language Summary (In Japanese).
Visual Summary: Visual Summary (In Japanese).

© The Author(s), 2022.
PMID 36312846
M Smith, D Hopkins, R C Peveler, R I G Holt, M Woodward, K Ismail
First- v. second-generation antipsychotics and risk for diabetes in schizophrenia: systematic review and meta-analysis.
Br J Psychiatry. 2008 Jun;192(6):406-11. doi: 10.1192/bjp.bp.107.037184.
Abstract/Text BACKGROUND: The increased prevalence of diabetes in schizophrenia is partly attributed to antipsychotic treatment, in particular second-generation antipsychotics, but the evidence has not been systematically reviewed.
AIMS: Systematic review and meta-analysis comparing diabetes risk for different antipsychotics in people with schizophrenia.
METHOD: We searched MEDLINE, PsycINFO, EMBASE, International Pharmaceutical Abstracts, CINAHL and Web of Knowledge until September 2006. Studies were eligible for inclusion if the design was cross-sectional, case-control, cohort or a controlled trial in individuals with schizophrenia or related psychotic disorders, where second-generation antipsychotics (defined as clozapine, olanzapine, risperidone and quetiapine) were compared with first-generation antipsychotics and diabetes was an outcome. Data were pooled using random effects inverse variance weighted meta-analysis.
RESULTS: Of the studies that met the inclusion criteria (n=14), 11 had sufficient data to include in the meta-analysis. Four of these were retrospective cohort studies. The relative risk of diabetes in patients with schizophrenia prescribed one of the second-generation v. first-generation antipsychotics was 1.32 (95% CI 1.15-1.51). There were insufficient data to include aripiprazole, ziprasidone and amisulpride in this analysis.
CONCLUSIONS: There is tentative evidence that the second-generation antipsychotics included in this study are associated with a small increased risk for diabetes compared with first-generation antipsychotics in people with schizophrenia. Methodological limitations were found in most studies, leading to heterogeneity and difficulty interpreting data. Regardless of type of antipsychotic, screening for diabetes in all people with schizophrenia should be routine.

PMID 18515889
A J Mitchell, V Delaffon, D Vancampfort, C U Correll, M De Hert
Guideline concordant monitoring of metabolic risk in people treated with antipsychotic medication: systematic review and meta-analysis of screening practices.
Psychol Med. 2012 Jan;42(1):125-47. doi: 10.1017/S003329171100105X. Epub 2011 Aug 10.
Abstract/Text BACKGROUND: Despite increased cardiometabolic risk in individuals with mental illness taking antipsychotic medication, metabolic screening practices are often incomplete or inconsistent.
METHOD: We undertook a systematic search and a PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) meta-analysis of studies examining routine metabolic screening practices in those taking antipsychotics both for patients in psychiatric care before and following implementation of monitoring guidelines.
RESULTS: We identified 48 studies (n=290 534) conducted between 2000 and 2011 in five countries; 25 studies examined predominantly schizophrenia-spectrum disorder populations; 39 studies (n=218 940) examined routine monitoring prior to explicit guidelines; and nine studies (n=71 594) reported post-guideline monitoring. Across 39 studies, routine baseline screening was generally low and above 50% only for blood pressure [69.8%, 95% confidence interval (CI) 50.9-85.8] and triglycerides (59.9%, 95% CI 36.6-81.1). Cholesterol was measured in 41.5% (95% CI 18.0-67.3), glucose in 44.3% (95% CI 36.3-52.4) and weight in 47.9% (95% CI 32.4-63.7). Lipids and glycosylated haemoglobin (HbA1c) were monitored in less than 25%. Rates were similar for schizophrenia patients, in US and UK studies, for in-patients and out-patients. Monitoring was non-significantly higher in case-record versus database studies and in fasting samples. Following local/national guideline implementation, monitoring improved for weight (75.9%, CI 37.3-98.7), blood pressure (75.2%, 95% CI 45.6-95.5), glucose (56.1%, 95% CI 43.4-68.3) and lipids (28.9%, 95% CI 20.3-38.4). Direct head-to-head pre-post-guideline comparison showed a modest but significant (15.4%) increase in glucose testing (p=0.0045).
CONCLUSIONS: In routine clinical practice, metabolic monitoring is concerningly low in people prescribed antipsychotic medication. Although guidelines can increase monitoring, most patients still do not receive adequate testing.

PMID 21846426
M De Hert, D Vancampfort, C U Correll, V Mercken, J Peuskens, K Sweers, R van Winkel, A J Mitchell
Guidelines for screening and monitoring of cardiometabolic risk in schizophrenia: systematic evaluation.
Br J Psychiatry. 2011 Aug;199(2):99-105. doi: 10.1192/bjp.bp.110.084665.
Abstract/Text BACKGROUND: Metabolic and cardiovascular health problems have become a major focus for clinical care and research in schizophrenia.
AIMS: To evaluate the content and quality of screening guidelines for cardiovascular risk in schizophrenia.
METHOD: Systematic review and quality assessment of guidelines/recommendations for cardiovascular risk in people with schizophrenia published between 2000 and 2010, using the Appraisal of Guidelines for Research and Evaluation (AGREE).
RESULTS: The AGREE domain scores varied between the 18 identified guidelines. Most guidelines scored best on the domains 'scope and purpose' and 'clarity of presentation'. The domain 'rigour of development' was problematic in most guidelines, and the domains 'stakeholder involvement' and 'editorial independence' scored the lowest. The following measurements were recommended (in order of frequency): fasting glucose, body mass index, fasting triglycerides, fasting cholesterol, waist, high-density lipoprotein/low-density lipoprotein, blood pressure and symptoms of diabetes. In terms of interventions, most guidelines recommended advice on physical activity, diet, psychoeducation of the patient, treatment of lipid abnormalities, treatment of diabetes, referral for advice and treatment, psychoeducation of the family and smoking cessation advice. Compared across all domains and content, four European guidelines could be recommended.
CONCLUSIONS: Four of the evaluated guidelines are of good quality and should guide clinicians' screening and monitoring practices. Future guideline development could be improved by increasing its rigour and assuring user and patient involvement.

PMID 21804146
Toby Pillinger, Robert A McCutcheon, Luke Vano, Yuya Mizuno, Atheeshaan Arumuham, Guy Hindley, Katherine Beck, Sridhar Natesan, Orestis Efthimiou, Andrea Cipriani, Oliver D Howes
Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysis.
Lancet Psychiatry. 2020 Jan;7(1):64-77. doi: 10.1016/S2215-0366(19)30416-X. Epub 2019 Dec 17.
Abstract/Text BACKGROUND: Antipsychotic treatment is associated with metabolic disturbance. However, the degree to which metabolic alterations occur in treatment with different antipsychotics is unclear. Predictors of metabolic dysregulation are poorly understood and the association between metabolic change and change in psychopathology is uncertain. We aimed to compare and rank antipsychotics on the basis of their metabolic side-effects, identify physiological and demographic predictors of antipsychotic-induced metabolic dysregulation, and investigate the relationship between change in psychotic symptoms and change in metabolic parameters with antipsychotic treatment.
METHODS: We searched MEDLINE, EMBASE, and PsycINFO from inception until June 30, 2019. We included blinded, randomised controlled trials comparing 18 antipsychotics and placebo in acute treatment of schizophrenia. We did frequentist random-effects network meta-analyses to investigate treatment-induced changes in body weight, BMI, total cholesterol, LDL cholesterol, HDL cholesterol, triglyceride, and glucose concentrations. We did meta-regressions to examine relationships between metabolic change and age, sex, ethnicity, baseline weight, and baseline metabolic parameter level. We examined the association between metabolic change and psychopathology change by estimating the correlation between symptom severity change and metabolic parameter change.
FINDINGS: Of 6532 citations, we included 100 randomised controlled trials, including 25 952 patients. Median treatment duration was 6 weeks (IQR 6-8). Mean differences for weight gain compared with placebo ranged from -0·23 kg (95% CI -0·83 to 0·36) for haloperidol to 3·01 kg (1·78 to 4·24) for clozapine; for BMI from -0·25 kg/m2 (-0·68 to 0·17) for haloperidol to 1·07 kg/m2 (0·90 to 1·25) for olanzapine; for total-cholesterol from -0·09 mmol/L (-0·24 to 0·07) for cariprazine to 0·56 mmol/L (0·26-0·86) for clozapine; for LDL cholesterol from -0·13 mmol/L (-0.21 to -0·05) for cariprazine to 0·20 mmol/L (0·14 to 0·26) for olanzapine; for HDL cholesterol from 0·05 mmol/L (0·00 to 0·10) for brexpiprazole to -0·10 mmol/L (-0·33 to 0·14) for amisulpride; for triglycerides from -0·01 mmol/L (-0·10 to 0·08) for brexpiprazole to 0·98 mmol/L (0·48 to 1·49) for clozapine; for glucose from -0·29 mmol/L (-0·55 to -0·03) for lurasidone to 1·05 mmol/L (0·41 to 1·70) for clozapine. Greater increases in glucose were predicted by higher baseline weight (p=0·0015) and male sex (p=0·0082). Non-white ethnicity was associated with greater increases in total cholesterol (p=0·040) compared with white ethnicity. Improvements in symptom severity were associated with increases in weight (r=0·36, p=0·0021), BMI (r=0·84, p<0·0001), total-cholesterol (r=0·31, p=0·047), and LDL cholesterol (r=0·42, p=0·013), and decreases in HDL cholesterol (r=-0·35, p=0·035).
INTERPRETATION: Marked differences exist between antipsychotics in terms of metabolic side-effects, with olanzapine and clozapine exhibiting the worst profiles and aripiprazole, brexpiprazole, cariprazine, lurasidone, and ziprasidone the most benign profiles. Increased baseline weight, male sex, and non-white ethnicity are predictors of susceptibility to antipsychotic-induced metabolic change, and improvements in psychopathology are associated with metabolic disturbance. Treatment guidelines should be updated to reflect our findings. However, the choice of antipsychotic should be made on an individual basis, considering the clinical circumstances and preferences of patients, carers, and clinicians.
FUNDING: UK Medical Research Council, Wellcome Trust, National Institute for Health Research Oxford Health Biomedical Research Centre.

Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
PMID 31860457
Davy Vancampfort, Christoph U Correll, Britta Galling, Michel Probst, Marc De Hert, Philip B Ward, Simon Rosenbaum, Fiona Gaughran, John Lally, Brendon Stubbs
Diabetes mellitus in people with schizophrenia, bipolar disorder and major depressive disorder: a systematic review and large scale meta-analysis.
World Psychiatry. 2016 Jun;15(2):166-74. doi: 10.1002/wps.20309.
Abstract/Text Type 2 diabetes mellitus (T2DM) is highly predictive of cardiovascular diseases and can have particularly deleterious health impacts in people with severe mental illness (SMI), i.e. schizophrenia, bipolar disorder or major depressive disorder. This meta-analysis aimed: a) to describe pooled frequencies of T2DM in people with SMI; b) to analyze the influence of demographic, illness and treatment variables as well as T2DM assessment methods; and c) to describe T2DM prevalence in studies directly comparing persons with each specific SMI diagnosis to general population samples. The trim and fill adjusted pooled T2DM prevalence among 438,245 people with SMI was 11.3% (95% CI: 10.0%-12.6%). In antipsychotic-naïve participants, the prevalence of T2DM was 2.9% (95% CI: 1.7%-4.8%). There were no significant diagnostic subgroup differences. A comparative meta-analysis established that multi-episode persons with SMI (N=133,470) were significantly more likely to have T2DM than matched controls (N=5,622,664): relative risk, RR=1.85, 95% CI: 1.45-2.37, p<0.001. The T2DM prevalence was consistently elevated in each of the three major diagnostic subgroups compared to matched controls. Higher T2DM prevalences were observed in women with SMI compared to men (RR=1.43, 95% CI: 1.20-1.69, p<0.001). Multi-episode (versus first-episode) status was the only significant predictor for T2DM in a multivariable meta-regression analysis (r(2) =0.52, p<0.001). The T2DM prevalence was higher in patients prescribed antipsychotics, except for aripriprazole and amisulpride. Routine screening and multidisciplinary management of T2DM is needed. T2DM risks of individual antipsychotic medications should be considered when making treatment choices.

© 2016 World Psychiatric Association.
PMID 27265707
Davy Vancampfort, Brendon Stubbs, Alex J Mitchell, Marc De Hert, Martien Wampers, Philip B Ward, Simon Rosenbaum, Christoph U Correll
Risk of metabolic syndrome and its components in people with schizophrenia and related psychotic disorders, bipolar disorder and major depressive disorder: a systematic review and meta-analysis.
World Psychiatry. 2015 Oct;14(3):339-47. doi: 10.1002/wps.20252.
Abstract/Text Metabolic syndrome (MetS) and its components are highly predictive of cardiovascular diseases. The primary aim of this systematic review and meta-analysis was to assess the prevalence of MetS and its components in people with schizophrenia and related psychotic disorders, bipolar disorder and major depressive disorder, comparing subjects with different disorders and taking into account demographic variables and psychotropic medication use. The secondary aim was to compare the MetS prevalence in persons with any of the selected disorders versus matched general population controls. The pooled MetS prevalence in people with severe mental illness was 32.6% (95% CI: 30.8%-34.4%; N = 198; n = 52,678). Relative risk meta-analyses established that there was no significant difference in MetS prevalence in studies directly comparing schizophrenia versus bipolar disorder, and in those directly comparing bipolar disorder versus major depressive disorder. Only two studies directly compared people with schizophrenia and major depressive disorder, precluding meta-analytic calculations. Older age and a higher body mass index were significant moderators in the final demographic regression model (z = -3.6, p = 0.0003, r(2)  = 0.19). People treated with all individual antipsychotic medications had a significantly (p<0.001) higher MetS risk compared to antipsychotic-naïve participants. MetS risk was significantly higher with clozapine and olanzapine (except vs. clozapine) than other antipsychotics, and significantly lower with aripiprazole than other antipsychotics (except vs. amisulpride). Compared with matched general population controls, people with severe mental illness had a significantly increased risk for MetS (RR = 1.58; 95% CI: 1.35-1.86; p<0.001) and all its components, except for hypertension (p = 0.07). These data suggest that the risk for MetS is similarly elevated in the diagnostic subgroups of severe mental illness. Routine screening and multidisciplinary management of medical and behavioral conditions is needed in these patients. Risks of individual antipsychotics should be considered when making treatment choices.

© 2015 World Psychiatric Association.
PMID 26407790
Ronald J Gurrera, John C Simpson, Ming T Tsuang
Meta-analytic evidence of systematic bias in estimates of neuroleptic malignant syndrome incidence.
Compr Psychiatry. 2007 Mar-Apr;48(2):205-11. doi: 10.1016/j.comppsych.2006.10.004. Epub 2007 Jan 2.
Abstract/Text OBJECTIVE: The aim of this study was to examine published reports for sources of excessive variance in neuroleptic malignant syndrome (NMS) incidence estimates.
DATA SOURCES: An unrestricted computerized MEDLINE search was conducted with a comprehensive search logic and supplemented by secondary references and a manual search of an extensive personal library.
STUDY SELECTION: Studies were analyzed if they presented original data and provided at least 2 of the following: number of NMS cases, number of patients at risk, or ratio of cases to patients at risk. Twenty-six of the 28 candidate studies met these minimal criteria.
DATA EXTRACTION: Variables included incidence, year of study publication, mean year of NMS occurrence, patient population at risk, study design, diagnostic criteria, and country of origin.
DATA SYNTHESIS: Standard error, which reflects study size, accounted for 90.8% of the variance (beta = .953, P < .001) in this international series of 26 NMS incidence estimates. Incidence was significantly lower in 7 studies the time end points of which were set in advance of case identification (chi(2) = 71.08, P < .001). No other variable was significantly related to incidence.
CONCLUSIONS: Neuroleptic malignant syndrome incidence estimates to date are non-trivially biased such that larger study size (patients at risk) is strongly related to lower observed incidence. Future studies can minimize the contribution of this and other sources of experimental error by incorporating several very feasible recommendations.

PMID 17292713
So Kirino, Mutsuki Sakuma, Fuminari Misawa, Yasuo Fujii, Hiroyuki Uchida, Masaru Mimura, Hiroyoshi Takeuchi
Relationship between polydipsia and antipsychotics: A systematic review of clinical studies and case reports.
Prog Neuropsychopharmacol Biol Psychiatry. 2020 Jan 10;96:109756. doi: 10.1016/j.pnpbp.2019.109756. Epub 2019 Aug 28.
Abstract/Text OBJECTIVE: This systematic review aimed to elucidate the relationship between polydipsia and antipsychotics.
METHODS: We systematically searched MEDLINE, Embase, and PsycINFO, and included clinical studies and case reports on polydipsia induced or improved by antipsychotics.
RESULTS: We identified 61 articles: 1 double-blind randomized controlled trial (RCT), 4 single-arm trials, 1 cross-sectional study, 3 case series, and 52 case reports. The double-blind RCT demonstrated no significant difference in improvement in polydipsia between olanzapine and haloperidol. Two single-arm trials showed that polydipsia improved during clozapine treatment, whereas the other 2 showed that risperidone did not improve polydipsia. The cross-sectional study showed the prevalence of hyponatremia with first-generation antipsychotics (FGAs: 26.1%) and second-generation antipsychotics (SGAs: 4.9%). Two case series reported that clozapine improved polydipsia; the other one indicated that patients with polydipsia who were treated with FGAs had schizophrenia (70.4%) and mental retardation (25.9%). Of 90 cases in the case reports, 67 (75.3%) were diagnosed with schizophrenia. Of 83 cases in which antipsychotic treatment started before the onset of polydipsia, 75 (90.3%) received FGAs, particularly haloperidol (n = 24, 28.9%), and 11 (13.3%) received risperidone. Among 40 cases in which polydipsia was improved following antipsychotic treatment, 36 (90.0%) received SGAs, primarily clozapine (n = 14, 35.0%).
CONCLUSIONS: Although the causal relationship between polydipsia and antipsychotics remains unclear because of the paucity of high-quality studies, antipsychotics with high affinity to dopamine D2 receptors may be associated with an increased risk of polydipsia while clozapine may be effective for treating polydipsia.

Copyright © 2019 Elsevier Inc. All rights reserved.
PMID 31472167
Mutsuki Sakuma, Fuminari Misawa, Midori Maeda, Yasuo Fujii, Hiroyuki Uchida, Masaru Mimura, Hiroyoshi Takeuchi
Development of diagnostic criteria and severity scale for polydipsia: A systematic literature review and well-experienced clinicians' consensus.
Psychiatry Res. 2021 Mar;297:113708. doi: 10.1016/j.psychres.2021.113708. Epub 2021 Jan 4.
Abstract/Text Despite the clinical importance of polydipsia, no diagnostic criteria or severity scales that comprehensively assess this condition are available. Thus, we aimed to develop diagnostic criteria and a severity scale for polydipsia based on a systematic review and well-experienced clinicians' consensus. We performed a systematic review, identified 27 studies related to diagnostic criteria or severity classification for polydipsia, and extracted items used to assess polydipsia in these studies. Ten well-experienced clinicians-5 psychiatrists and 5 nurses-participated in the Delphi method. They evaluated 39 items extracted based on the results of the systematic review regarding (1) their necessity in diagnosing and assessing the severity of polydipsia, and (2) their relative importance rated on 7-point scale among the items included in the severity scale. The Polydipsia Diagnostic Criteria (PDC) included 4 essential items-excessive drinking, low serum sodium level or low serum osmolality, abnormal normalized diurnal weight gain, and low urine specific gravity-based on consensus reached using the Delphi method. The Polydipsia Severity Scale (PSS) included 13 items with a maximum score of 59. The first diagnostic criteria and symptom scale for polydipsia were developed based on the findings of a systematic review and well-experienced clinicians' consensus.

Copyright © 2021. Published by Elsevier B.V.
PMID 33461119

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